This proposal is primarily a study of treatment efficacy with related implications for the underlying pathophysiology of major depressive disorder (MDD), in a well defined group of patients with MDD. We propose to programmatically develop a large study population of patients with MDD classified with respect to HPT abnormalities and response a selective serotonin reuptake inhibitor (SSRI) antidepressant treatment, both retrospectively and prospectively. Such a cohort will allow the examination of the role of the HPT axis in the pathophysiology and heterogeneity of MDD.